Alkyl-n-[alpha, alpha-dimethyl-beta-(p-halophenyl)-ethyl]-carbamates and compositions thereof



United States Patent '0 Claims. C1. 16755) The present invention relatesto a new group of'chemical compounds N(phenylethyl)-carbamic acidesters, characterized by improved properties as appetite curtailingagents and to processes for their manufacture. application is acontinuation-in-part of application Serial No. 208,933, filed July 10,1962, now abandoned.

Amines having a sympathomimetic action have been This 5 used and arebeing used forcurtailing appetite, i.e., as p appetite-reducing agents.Examples of such amines are: amphetamine, metamphetamine, phentermine,and chlorophentermine. Unfortunately, these amines possess definitelyunpleasant side reactions, such as a blood pressure increasing effect,.aheart beat rate increasing effect, reduction of intestinal motility,gastric distress, excitation of the central nervous system producingjitteriness, nervous tension, loss of sleep, and euphoria, etc. andfurther danger ofaddiction, particularly because of the central nervoussystem excitation, has to be .taken into account. 7

For these reasons, it has been conventional to administer these aminecompounds in a form in which the active substance is only liberatedslowly into the gastrointestinal tract. While the side effects arereduced in this manner so is the desired reduction in appetite.

It has now surprisingly been found that if the hydrogen atom attached tothe nitrogen atom in certain of the amines of the above type issubstituted for by a carbalkoXy radical, compounds characterized bysubstantially less pronounced side effects and in which the appetitereducing effect is not impaired substantially are obtained.

Because the toxicity is considerably reduced a class of compounds isthus made available which has a greater therapeutic range and is thusmuch safer to administer. Thus, it has been found that-in the compoundsso sub- 'stituted, the excitory effect on the central nervous system isreduced to such a degree that the compounds no longer possess ameasurable excitory action even when they are administered in lethaldoses.

The substituted N-(phenylethyl) carbamic acid esters of the inventionare represented by the following general formula wherein R representshydrogen or halogen and R represents a straight-chain alkyl radical offrom 1 to 3 carbon atoms. Included in the group R are chlorine, bromine,fluorine, and the like.

in which R is as above-defined, either, directly with a chloroformicacid ester of the general formula CICOOR in which R is as above definedor with'the corresponding carbonic acid dialkyl ester. Alternatively, anamine of the general Formula II (above) can be first converted into itscorresponding urea derivative andthe derivative thereafter reacted withan alcohol, or an amine of Formula II (above) can be convertedwithph'osg'ene into the correspondingcarbamic acid chloride which isthen'reacted either directly with the corresponding alcohol or convertedby splitting ofi hydrogen halide into the corresponding 'isocyanate andthen reacted with-RiOH. 1 A part of the starting amines used in thepreparation ofthe compounds of the invention'have not as yet beendescribed in the literature. -However, they may easily be obtained byprocedures known per se. Thus, for example, by the conversion of acorresponding alcohol of the general formula I o m f...

.F OHPMH with hydrocyanic acid or with an alkali-cyanide in the presenceof a strong acid and glacial acetic acid, there is formed, first of alla formamide-of the general formula:

v CH3 H EXAMPLE 1 Ethyl-N-[aux-dimeflryl-fl-phenylethyl] carbamate Asolution of 11.3 g. of ethyl chloroformate in 15 ml. of diethyl ether isintroduced dropwise into a solution of 29.8 g. ofa,a-dimethyl-fl-phenylethyl amine in 150 ml. of diethyl other withstirring-and cooling with ice. Half the quantity of amine introducedprecipitates as hydro- In accordance with the present invention, thesubsti tuted N-(phenylethyl)-carbamic acid esters can be prepared by anumber of alternate, but equivalent reactions: the newN-(phenylethyl)-carbamic acid esters can be prepared by reacting anamine of the general formula:

c In (II) chloride, which is suction-filtered and washed with ether.After concentrating the combined mother liquorsby evaporation anddistilling under high vacuum, 21.3 g. (=95% of the theoretical of thequantity of reacted amine) of ethyl N-(a,a-dimethyl-B-phenylethyl)-carebamate are obtained with a B.l. of 77 C; I

, EXAMPLE 2 A solution of 12.3 g. of a,a-dimethyl-8-(p-chlorophenyl)ethylamine in m1. of alcohol is quickly added to asolution of 8.2 g. of ethyl chloroforrna'te in 80 mL of ethyl alcohol(96%) with stirring and ice cooling, then a saturated aqueous solutionof7 g. of potassium bicarbonate is added during 20 minutes and stirring iscontinued for another 2 hours at room temperature. After distilling offthe alcohol in vacuum, extracting the oily residue with ether, dryingthe ethereal phase over sodium sulphate and distilling under;highvacuum, 15.9 g. (=92% of the theoretical) of ethyl N-[ x, x-dimethyl-B-(p-chlorophenyl)-ethyl]-carbamate are obtained with a BR of 8890 C.and an MP. of 52.553 C.

3 EXAMPLE 3 Ethyl-N-[u,u-dimethyl-fl-(p-chlorophenyl) ethyl]carbamate6.3 g. of a,x-dimethyl-fl-(p-chlorophenyl)-ethyl isocyanate are mixedwith ml. of absolute alcohol and after standing for several hours, themixture is concentrated by evaporation and distilled under high vacuum.6.6 g.=86% of the theoretical are obtained.

The a,a-dimethyl-fi-(p-chlorophenyl)-ethyl isocyanate used as startingproduct is prepared as follows:

A solution of a,a-dimethyl-fl-(p-chlorophenyl)ethyl amine in ethylenechloride is slowly added dropwise to a solution of phosgene in ethylenechloride while stirring and cooling with ice. After filtering off theprecipitate (hydrochloride of the initial amine) and vacuumconcentration of the filtrate, the residue is extracted with petrol. Theresidue which is insoluble in petrol consists of the starting amine andN,N-bis-[a,a-dimethyl-B-(pchlorophenyl)-ethyl]urea (M.P. 214-215C.)..The petrol solution is concentrated by evaporation.a,a-Dimethylfi-(p-chlorophenyl) ethyl isocyanate, which is not isolatedbut is further processed 'as indicated above, remains as residue.

EXAMPLE 4 n-Pr0pyl-N[a,a-dimethylfi-(p-chlorophenyl) ethyZ]-carbamateThis is obtained from 18.4 g. of a,ot-dimethyl-B-(pchlorophenyl)ethylamine and 6.3 g. of n-propyl chloroformate, in a manner analogousto Example 1. B.P. 119121 C. Yield: 10.8 g. (=80% of the theoretical).

C. Yield: 32.8 g.=75.5% of the theoretical.

EXAMPLE 6 (A) a,a-Dimethyl-[3-[p-bromio-phenyl]-ethylamine hydrochloride2.5 g. sodium-cyanide are dissolved with strong cooling and stirring inglacial acetic acid and to the resulting solution there is added indropwise fashion a mixture of 6 ml. glacial acetic acid and 12 g.concentrated sulfuric acid. Thereafter, still dropwise, and under slightWarming, 10.5 g. a,a-dimethyl-p-bromophenyl-ethyl-alcohol is added andthe mixture thereby produced moderately heated for sometime. Thereaction solution is thereafter poured onto ice, neutralized with sodaand extracted with ether. The ethereal extract is dried using sodiumsulfate and the ether evaporated. TheN-[a,a-dimethyl-(p-bromophenyl)-ethyl]-formamide thereby obtained isboiled without isolation or purification with substantially concentratedhydrochloric acid for one hour and then extracted with ether. Theaqueous phase is alkalinized with soda lye. After repeated extractionswith ether and drying, the free base is precipitated with etherealhydrochloric acid as the hydrochloride. The melting point of thehydrochloride is 241242 C. (isopropanol). The (1,0:-dimethyl-B-[p-bromophenyl]-ethylamine hydrochloride is obtained in ayield amounting to 70.5% of theory.

(B) N- [a,a-dimethyl-(p-bromophenyl) -ethyl]-carbamic acid ethyl ester6.6 g. a,a-dimethyl- 3-[p-brornophenyl]-ethylarnine are dissolved in 34ml. alcohol and under stirring and with ice cooling, rapidly combinedwith a solution of 3.38 g. chloro-formic acid ethyl ester in 34 ml.alcohol. To the resulting mixture there is added in dropwise fashion asaturated aqueous solution of 3 g. potassium hydrogen carbonate withcooling and with 3 hours of stirring. The

alcohol is distilled off in vacuo. The residue is extracted with ether,dried over sodium sulfate, concentrated by evaporation and distilled.The boiling point of the N- [0a,ot dimethyl(p-brornophenyl)-ethyl]-carbarnic acid ethyl ester at 2.l0 mm. Hg is 92C.; the melting point amounts to 6364 C. The yield of recovered esteramounts to 5.2 g. (59.8% of theory).

EXAMPLE 7 (A) a,a-dimethyl-fi-[p-fluorophenyl]-ethylamine In the mannerdescribed in Example 6, 44.1 g. of a edimethyl-[p-fiuorphenyl]-ethylalcohol are converted with 14.5 g. sodium-cyanide in sulfuric acid/glacial acetic acid into N-[a,a-dimethyl-(p-fiuorophenyl)-ethyl]-formamide which is not isolated, but, as described above, hydrolizedwith concentrated hydrochloric acid using heat in the hydrolysis.Following alkalinization of the resulting reaction solution, the freeamine is extracted with ether, the ethereal solution obtained dried,evaporated, and the residue fractionally distilled. The boiling point ofthe a,a-dimethyl-/3-(p-fiuorophenyl)-ethy1amine at 4 mm. Hg is 67 C.; 111.4942. The corresponding hydrochloride has a melting point of -186 C.The a, x-dimethyl/8-(p-flu0rophenyl)-ethylamine is recovered in an 82.5%of theory yield.

(B) N- [zx,oc-dimelhyl- (p-fluorophenyl) -etl1yl] -earbamic acid ethylester There are added dropwise and under stirring and ice cooling to asolution of 5.77 g. chloroformic acid ethyl ester in 58 ml. alcohol, asolution of 8.25 g. a,w-dimethyl {3-[p-fiuorophenyl]-ethylamine in 58ml. alcohol. Stir= ring and cooling are continued and a saturatedaqueous solution of 5.05 g. potassium bicarbonate is added to theresulting mixture over a period of 20 minutes. After 3 hours ofstirring, followed by vacuum distillation of the alcohol, the residue istaken up in ether, dried over sodium sulfate, evaporated and the residuethereby obtained dis tilled. The boiling point of theN-[m,a-dimethyl-(pfiuorophenyl)-ethyl]-carbamic acid ethyl esterobtained amounts at 2.1O mm. Hg 87 C. The ester is recovered in anamount of 7.2 g. representing 61.4% of theory.

The compounds of the invention, as noted above, are preferablyadministered orally in tablets, elixers in conjunction with suitablecarriers and other types of oral pharmaceutical dosage units. Whereparenteral administration is indicated, the compounds are prepared insterile solutions or suspensions.

A preferred form of administration is a capsule or tablet. The capsulemay be of either the hard shell or soft shell type, is generally ofgelatin, although any water-soluble capsulating material that willdistintegrate after oral administration is suitable. Lubricants, such asmagnesium stearate and anticaking agents to keep the drug in readilydispersible form may be incorporated in the dosage unit. When tabletsare prepared, they may be made in various sizes. These are generallycompounded with binding agents, lubricants, and other substances whichare commonly used in tablet manufacture, such as magnesium stearate,stearic acid, talc, corn starch, lactose, or the like. If desired, thesetablets may be coated with sugar or sugarlike preparations in accordancewith the common practices in the tablet manufacturing art.

The compounds in accordance with the invention are primarilyanorexigenic in action. They produce significant and progressive weightloss by voluntary restriction of caloric intakes. They are effective tocurtail appetite without producing jitteriness, nervous tension, ordisturbance of sleep of the dieting patient. They are notable for theirlack of effect on blood pressure or cardiac rhythm.

The compounds in accordance with the invention have been compared withcertain of the known compounds for the purpose of establishing therelatively greater effectiveness of the compounds in accordance with theinvention as diet control agents. The compounds in accordance with theinvention, while efiect-ive to control appetite, haveremarkably-low'toxicity and do not tend to produce physiologicaldisturbances, such as those-mentioned above in connection with the knowncompounds.

The comparative data have been incorporated into a table hereinafter setforth; In this table, the appetitecurtailing effect, toxicity (LD) andmotility increasing activity of a numberof carbamic acid esters inaccordance with the invention are shown in comparison with those of thecorresponding amines. All ofthe experiments were carried out on rats towhich the substances were administered orally. (ll-Amphetamine was usedas'the standard substance. The .per diem dose which reduced the foodconsumption 'of the experimental animals over 5 days by an average of40% is designated as Deff 40% (column 2). Column 3 shows the-toxicityvalues -(LD values) after a single, oral application. These are thevalues which were established after completing the post mortem, during a14-day observation period. In columnA there are shown the therapeuticratios which can be calculated from the LD and Delf 40% values. Column 5shows themotility increasing activity in comparison. with amphetamine.The :motility increasing frequency wasdetermined bythe method of R. KopfD. Lorenz. I. Moller Nielsen: Naunyn-Schmiedebergs-Arch. exp. Path.Pharmakol. 241, 1-85 (1960). This is expressed as the dose which doublesthe motility after a single oral application by comparison with acontrol group. In the case of amphetamine, the corresponding dose was6.5 mg./kg. .The doses of the other substances which have the sameeffect are substantially. higher, so that the activity based onamphetamine=100 is correspondingly smaller.

It can clearly be seen from the table that the motilityincreasingactivity decreases considerably in all cases. In

addition, most of the examples show an increase in therapeutic rangewhichis sometimes considerable.

Particularly thorough pharmacological and toxicological investigationswere carried out in connection with the compound ethyl-N- [u,a-dimethyl-B- (p-chlorophenyl -ethyl]-carbarnate. This compound has aprolonged, i.e. long lasting effect in curtailing appetite. A singleapplication of 29 mg./kg., produced complete inhibition of foodconsumption of rats for 6 hours and even after 12 hours, the foodconsumption was still considerably reduced. When dl-amphetamine wasused, however, the anorexia produced and there responsible for thecurtailment of food intake with an equi-molar dose had subsided com- Inchronic toxicity tests carried out on 20 rats, the active substance wasmixed in a concentration of 0.03% with the standard food. Dailyconsumption of active substance by the animals in this case was between20 and 30 mg./kg. and the period of the experiment was weeks. In thefirst 5 weeks of the experiment, the increase in the body weight laggedbehind that of the control animals by about 20% because of their smallconsumption of food. After that body weight development proceededconcurrently and, after about 20 weeks approached the weights of thecontrol animals to an increasing degree. In addition, chronic toxicitytests were carried out on 5 rabbits, the active substance being admixedin the food in a concentration of 0.075%. The amount of active substanceingested was similarly'20-30 mg./kg. During a 28-week feeding period,the behavior of theanimal's did not differ from that of the'controlanimals, apart from an initial period of unchanged weight. Repeatedchecks on the functioning of the liver, using the sulfobrornophthaleintest, gave no indication of a hepatotoxic action.

Checks carried out'at inte rvals'of 68 weeks on the bloodpicture andurine showed no difference from the normal with both types of animals.Histological investigations carried out during and on completion of thetest on dead animals showed no sign of disease. During the clinicaltesting of ethyl-N-[a,ot-dimethyl-[3-(p-chlorophem yl)-ethyl]-carbamate(partly in an open test, and partly in a blind test and double blindtest) doses of 30 mg., 1-3 times per day, and later 90 mg, once or twicea day, were administered over 412 weeks to about 250 stationary andambulatory patients. The weekly decrease in weight was at least 500 g.(maximum 2.5 kg. per week). Investigations carried out on the bloodpicture, hypostasis, blood pressure, pulse frequency, and on the urinefor albumin, sedimentatiomsugar and urobilinogen showed no changes fromthe normal values.

The liver function was evaluated (Takata-Ara, Weltmann-Band, cadmium andthymol turbidity test) in 15 patients and demonstrated no pathologicaldeviation from the normal values. Experiments on function as well asbiopsies of the liver tissue, carried out with 5 serious chronicsufferers from liver complaints, showed no deterioration in the resultsafter administration of 30 mg. of ethyl N-[a,ot-dimethyl f8(p-chlorophenyl)-ethyl]-carbamate twice a day for 68 weeks. Thesubjective compatibility was good.

TABLE Deli 40% LD Motility Compound LDsoZ Dcfi (Amphetamine 40% 01MgJkg. Mel/kg. Mg./lrg. Mol/kg.

dl'Amphetamine 18 23 1, 3 100 0., a-Dimethyl-fl-phenylethyl amine(Phentermin) 20 107 90 480 4, 5 5 Eth 'l-N- -Dimeth lhenyleth lcaibamiii i if? 1 50 226 200 904 4. 2 1 a, u-Dimethv1B(p-chlorophenyl)-eth ylamine (Chlorophentemiiue) 15 09 30 1, 050 15 4Ethyl-N-I a, u-Dimethyl-fl-(p-chlorophenyD- ethyl1-carbamate 19 74 6002, 340 3-3 2 Pronyl-N-[ a, a-Dimeth yl-fi-(p-chlorophen y1)-ethyH-carbamate 3 80 2. 022 19 0, ()2

We claim:

pletely after 6 hours. Experimental determinations of the blood pressurecarried out on despinalized rats, narcotized guinea pigs, and narcotizedcats demonstrated that with intravenous administration, asympathomimetic activity in the form of an increase in blood pressure orcontraction of the nictating membrane was not detectable. On oraladministration, a sympathomimetic action was observed when the pupiltest was performed on the rats. However, this only manifested itselfslowly. Circulatory phenomena, such as increased heart rate or a flushedfeeling, which generally occurs just after sympathomimetics have beentaken orally, are not apparent, this having been confirmed by clinicaltests.

1. A compound of the class having the structural formula wherein R ishalogen and R is aa straight chain lower alkyl group having from 1 to 3carbon atoms.

2. Ethyl-N- a,a-dirne'thyl-/5'-(p4chlorophenylethyl1 -carbamate.

3. n propyl N [a,;x-dimethyl-fi-(p chlorophenyl)- ethyl]-carbamate.

4. Methyl N [a,u-dimethyl-fi-(p chlorophenyl)- ethyl] -carb amate.

5. N-[a,a dimethyl-(p-bromophenyl)-ethyl]-carbamic acid ethyl ester.

6. N-[o,ot dimethyl (p fluorophenyl)-ethyl]-carbamic acid ethyl ester.

7. A therapeutic composition in effective dosage unit form useful forcurtailing appetite comprising a chemical compound of a class having thestructural formula:

wherein R is halogen, and R is a straight chain lower alkyl groupcontaining from 1-3 carbon atoms as active ingredient admixed with aphysiologically acceptable solid carrier.

10. A method of curtailing appetite which comprises administering to adieting patient a therapeutic composition in effective dosage unit formcomprising a compound having the structural formula:

wherein R is halogen, R is a straight chain lower alkyl group havingfrom 1-3 carbon atoms, as active ingredient combined with apharmaceutical carrier.

References Cited by the Examiner UNITED STATES PATENTS 2,041,733 5/1936Werntz 260471 2,651,658 9/1953 Bohl 260-471 FOREIGN PATENTS 672,9713/1939 Germany.

OTHER REFERENCES American Journal of Pharmacy, vol. 134, page 22.

Marsh, Chemical Abstracts43, 759d (1949).

Optiz, Chemical Abstracts 55, 8658f (1961).

Bougault et al., Compt. Rend 213, 310-313 (1941).

Gutsche et al., J. Am. Chem. Soc. 79, 4441-4448 (1951).

Bennington et al., J. Org. Chem. 23, 1979-1984 (1958).

Burger, Medicinal Chemistry (1960 edition) pages 598- 599.

Rinkes, Rec. Trav. Chim. 46, 268277 (1927).

LORRAINE A. WEINBERGER, Primary Examiner.

DANIEL D. HORWITZ, Examiner.

L. A. THAXTON, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3, 308,019 March 7, 1967 Rudolf Kopf et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

'In the heading to the printed specification, line 6, for "KleinhurdenPost" read Kleinhurden Post Immekeppel line 8, for "assignors to TroponDinklage E Co." read assignors to Tropon Werke Dinklage E Co. column 2,lines 43 and 58, and column 3, lines 3 and 36, for "ethyl]carbamate",each occurrence, read ethyl] carbamate column 3, line 12, for "a,q,dimethyl-B-(p-chlorophenyl) ethyl" reada,a-dimethyl-B-(p-chlorophenyl)ethyl line 26, for "n-Propyl-N[a,c-dimethyl-B(p-chlorophenyl)" read n-Propyl-N-[a;u-dimethyl-B(p-chlorophenyl) column 4, line 67, for "intakes" readintake column 6, line 70, for "aa" read a line 72, for"(p-chlorophenylethyl" read (pch1oropheny1)ethyl column 7, lines 27 to31, the formula should appear as shown below instead of as in thepatent:

R CH NH-C-O-R column 8, line 27, for "(1951)" read (1957) Signed andsealed this 28th day of November 1967.

(SEAL) Attest:

EDWARD M.,FLETCHER,JRO EDWARD J. BRENNER Attesting Officer Commissionerof Patents

1. A COMPOUND OF THE CLASS HAVING THE STRUCTURAL FORMULA
 10. A METHOD OFCURTAILING APPETITE WHICH COMPRISES ADMINISTERING TO A DIETING PATIENT ATHERAPEUTIC COMPOSITION IN EFFECTIVE DOSAGE UNIT FORM COMPRISING ACOMPOUND HAVING THE STRUCTURAL FORMULA: